rs3807153

Variant names:

• chr7-138733046-A-C
• rs3807153
• NM_020632.3:c.1739T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-138733046-A-C
• chr7-138733046-A-G
• chr7-138733046-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020632.3(ATP6V0A4):​c.1739T>G​(p.Met580Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M580I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

ATP6V0A4 Gene-Disease associations (from GenCC):

• renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive distal renal tubular acidosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.1739T>G	p.Met580Arg	missense_variant	Exon 17 of 22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.1739T>G	p.Met580Arg	missense_variant	Exon 16 of 21		NP_570855.2
ATP6V0A4	NM_130841.3	c.1739T>G	p.Met580Arg	missense_variant	Exon 16 of 21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1739T>G	p.Met580Arg	missense_variant	Exon 17 of 22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;D;.;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;.;M
PhyloP100		9.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D;D;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D
Polyphen		0.96	D;D;D;.;.;D
Vest4		0.79
MutPred		0.81		Loss of stability (P = 0.0371);Loss of stability (P = 0.0371);Loss of stability (P = 0.0371);.;.;Loss of stability (P = 0.0371);
MVP		0.93
MPC		0.79
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.91
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3807153; hg19: chr7-138417791;